GnRH-I (in the literature generally referred to as “GnRH”) is a small 10 amino acid long peptide (decapeptide) from the hypothalamus. The amino acid sequence of GnRH-I (SEQ ID NO: 1) can be represented by the following three-letter code:pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2or the corresponding one letter code where pE is pyroglutamic acid and # is amide:pE H W S Y G L R P G#.
GnRH-I acts at the hypophysis to cause an increase in release of biologically active Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone (LH) in the blood, which in turn stimulate the development of the testes in the growing male animal and the synthesis of male steroids. In the growing female animal the development of the ovaries is stimulated, as is the development of follicles within the ovary, synthesis of female steroids, and ovulation.
It is known that GnRH-I, if coupled to a carrier protein, can be used to vaccinate animals. Such a vaccination can be carried out for various reasons, all of which are connected with the natural function of the GnRH-I. As is known, a drastic reduction of LH and/or FSH in the blood inhibits the production of male steroids or androgens and sperm in the testis of the male and the formation of female steroids or progestogens and estrogens and follicle maturation in the ovary of the female. Such a reduction in the amounts of androgens, progestogens and estrogens in the blood, to a level comparable to that obtainable by removing the testes or ovaries via castration, can be achieved by effective immunization of the animal against GnRH-I. In male animals, in many cases the testes then appear to develop slowly or not at all, with no synthesis of androgens (male steroid hormones) and no formation of spermatozoa. In female animals the activity of the ovaria appears to diminish, with no synthesis of estrogens and progestogens (female steroid hormones), and inhibition of ripening of follicles and ovulation.
Recently it was reported that a second form of GnRH (GnRH-II) is present in primate brain (Lescheid et al., Endocrinol. 138 (1997) 5618-5629) and a gene for this second GnRH molecule was cloned from a human genomic library (GnRH-II, (SEQ ID NO: 2) (White et al., PNAS USA 95 (1998) 305-309). Mammalian GnRH-I (SEQ ID NO: 1) is hardly expressed outside the brain. A few exceptions are known in this respect. GnRH I is present in the endometrium of women with a menstrual cycle (Casan et al. Fertil. Sateril. 1998, 70, 102-106) and is expressed during pregnancy in the human placenta (Kelly et al., DNA cell Biol. 1991, 10, 411-421). GnRH mRNA was found in ovary, testis, thymus, placenta and hypothalamus of the rat (Oikawa et al., Endocrinology, 1990, 127, 2350-2356). Expression of GnRH was detected in immune tissue (spleen, thymus and lymphocytes) of pigs (Weesner et al., Life Sci, 1997, 61, 1643-1649).
GnRH-II is expressed in many tissues outside the brain, and is found in especially high concentrations in the kidneys, bone marrow and prostate. The presence of GnRH-II in diverse tissues other than the brain suggests that GnRH-II may have multiple functions. In addition, the strictly conserved structure of the GnRH-II peptide throughout diverse vertebrate species suggests that this neuropeptide possesses vital bioactivities. Until now, however, the functions of GnRH-II have been practically unknown. Several types of differentiated lymphocytes, such as T- and B-lymphocytes and mast cells, produce GnRH and GnRH-like peptides. Significant numbers of the latter cell type are present in the kidney, bone marrow and prostate, perhaps contributing to the high GnRH-II expression in these tissues. GnRH II seems less involved in reproduction as compared to GnRH-I. In the hypogonadal mouse, mouse which lacks the GnRH-I gene, GnRH-II producing cells are present in the same distribution as in a normal mouse, but this is not sufficient to cause normal gonadal development in these mice (Chen et al., FEBS Letters 435 (1998) 199-203). However, macaques in luteal phase of the menstrual cycle showed a marked increase in plasma luteinizing hormone concentrations after intravenous administration of GnRH-II, but this increase could not be induced during the mid follicular phase (Lescheid et al., Endocrinol. 138 (1997) 5618-5629).